Novartis Announces Strong Efficacy of First-in-Class Oral Factor B Inhibitor LNP023 in Paroxysmal Nocturnal Hemoglobinuria (PNH)

August 30, 2020 News /BioValleyBIOON/ --NovartisNovartis recently presented new data from the Phase II clinical study (NCT03439839) of LNP023 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) at the 2020 European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting, held online. LNP023 is a first-in-class, oral, potent, and selectiveComplement Factor B (FB) InhibitorPNH is a rare, life-threatening blood disorder characterized by complement-mediated hemolysis, thrombosis, and impaired bone marrow function, leading to debilitating symptoms that can significantly impair patients' quality of life.。

The results presented at the meeting showed that, despite treatment with the complement C5 inhibitor Soliris (eculizumab), hemolysis remained active.Anemia, among PNH patients requiring red blood cell transfusion,LNP023, as an add-on therapy to Soliris, significantly improved hematologic responses and increased hemoglobin levels.Discontinuation of Soliris and continued monotherapy with LNP023 resulted in 7 out of 10 patients maintaining hemoglobin levels and disease activity control.BiomarkerNo signs or symptoms of worsening or breakthrough hemolysis.

“The chief investigator of the study, Professor at the University of Naples Federico II in Italy and Head of the Hematology and BMT Department at Ospedale Moscati, stated: ‘This study shows that oral LNP023 treatment can avoid transfusions and provide meaningful clinical benefits in PNH patients who remain anemic and transfusion-dependent despite receiving standard-of-care anti-complement therapy. These data clearly demonstrate that’”LNP023 can control the hemolytic mechanism of this disease and has the potential to transform the treatment paradigm for PNH.。”

NovartisJohn Tsai, Global Head of Drug Development and Chief Medical Officer, stated, “These positive Phase II results are promising and pave the way for further evaluation of oral LNP023 as a potential monotherapy and standard of care for PNH. We will continue to develop LNP023 in this disease while exploring its application in a range of other complement system-mediated conditions.”

Chemical Structure of LNP023 (Image source: medchemexpress.com)

LNP023 is a first-in-class, oral, potent, and selective complement factor B (FB) inhibitor that directly, reversibly, and with high affinity binds to human complement factor B.Complement factor B is a component of the alternative pathway of the human immune complement system. Currently, LNP023 is in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and various kidney diseases involving the complement system with significant unmet medical needs, including IgA nephropathy, C3 glomerulopathy (C3G), atypical hemolytic uremic syndrome, and membranous nephropathy.

In PNH, LNP023 acts upstream of the terminal complement pathway at C5, preventing both intravascular and extravascular hemolysis. By targeting the underlying pathophysiology, LNP023 may offer therapeutic advantages over the current standard of care. Currently,NovartisAnother Phase II study (NCT03896152) is also underway to evaluate LNP023 as monotherapy in C5 inhibitor-naïve patients with paroxysmal nocturnal hemoglobinuria (PNH), with a Phase III study planned for launch later this year. In the United States and the European Union, LNP023 has been granted orphan drug designation (ODD) for the treatment of PNH and C3 glomerulopathy (C3G).

Complement Activation Cascade—A Therapeutic Modulation Target in PNH(Image source: PMC6060635,Click the image to view a larger version）

The Phase II study (NCT03439839) presented at this meeting is a multicenter, open-label, sequential two-cohort trial designed to evaluate the safety, efficacy, tolerability, and pharmacokinetics/pharmacodynamics of LNP023 in patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience active hemolysis and require red blood cell transfusions despite treatment with the C5 complement inhibitor Soliris (eculizumab) (Cohort 1: n=10). The primary objective of the study is to assess the effect of adding LNP023 to standard-of-care treatment (Soliris) on reducing hemolysis at Week 13. In this study, after 13 weeks of LNP023 treatment, patients may enter a long-term extension phase, during which modification or discontinuation of Soliris treatment is permitted at the investigator’s discretion.

Data presented at the meeting showed that, among PNH patients who continued to experience active hemolysis despite treatment with Soliris,LNP023 Treatment Improved Hematologic Responses and Biomarkers of Disease Activity。Adding LNP023 to Soliris treatment, patients' lactate dehydrogenase (LDH, intravascular hemolysisBiomarker) levels were significantly reduced, and hemoglobin (Hb) levels were significantly improved.

Compared with baseline values for Soliris monotherapy, LNP023 increased hemoglobin (Hb) levels by 2.87 g/dL (p < 0.001). With the exception of two patients, the remaining patients (80%) achieved Hb levels ≥ 12 g/dL without transfusion. Prior to LNP023 treatment, all patients required red blood cell transfusions.

To date, following at least 6 months of stable add-on therapy with LNP023, seven patients (70%) have discontinued Soliris and continued on LNP023 monotherapy, as determined by the investigators. Importantly, hemoglobin (Hb) levels remained stable in all patients receiving LNP023 monotherapy, with no signs of disease activityBiomarkersNo changes, nor any signs or symptoms of breakthrough hemolysis.

LNP023 also demonstrated a favorable safety and tolerability profile, with no serious treatment-related infections or thromboembolic events. After the data cutoff date, one participant who had severe lymphopenia at baseline discontinued treatment due to a serious adverse event (AE) of lymphoproliferative disorder. The most common adverse events were headache, insomnia, rhinitis, and rhinorrhea. (Bioon.com)

Original Source: Novartis announces positive results from Phase II study of LNP023 in patients with paroxysmal nocturnal hemoglobinuria (PNH)